Alkylaminoalkyl benzoates



Patented Feb. 14, 1950 ALKYLAMINOALKYL BENZOATES Arthur C. Cope,Belmont, Mass., assignor to Shari & Dohme, Incorporated, Philadelphia,Pa., a corporation of Maryland No Drawing. Original application May 31,1944,

Serial No. 538,201. Divided and this application December 21, 1946,Serial No. 717,817

1 Claim.

This invention relates to benzoic acid esters of (open-chain)secondary-alkyl(secondary) aminopropanols and -butanols, in which the(openchain)secondary-alkyl group is wholly hydrocarbon and has a totalof less than eleven carbon atoms. These esters are useful as localanesthetics, in general, combining high effectiveness with relativelylow toxicity, and are relatively non-irritating.

The compounds of the invention are represented by the general formula O0 ORINHR in which R represents a hydrocarbon (openchain)secondary-alkylgroup attached to the amino nitrogen and having a total of less thaneleven carbon atoms, and R1 represents the divalent alkylene group,residue of the propanol or butanol, and has a total of from three to sixcarbon atoms and with at least two and less than four carbon atomslinkedin sequence between the nitrogen and the oxygen.

Thus, it is seen that both the alkyl substituent on the amino group andthe amino group itself are secondary, and that the secondary amino groupis derived from ammonia by replacing one of its hydrogens by thehydrocarbon (openchain)secondary-alkyl substituent and a second hydrogenby the alkylene group. Accordingly, in this specification and intheclaim the expression (open chain) secondary alkyl (secondary)- amino isused to describe the alkyl-amino grouping on the propanolandbutanol-amine portion of the ester compounds of the invention and toshow that the amino group is always secondary and that the alkylsubstituent on the amino group is open-chain and always secondary as oneof its intermediate carbons is linked to the nitrogen. The(open-chain)secondary-alkyl substituent on the amino group of thealkylaminoalkanol portion of the compounds of the invention contains atleast three and less than eleven carbon atoms as in the isopropyl,secondary-butyl, -pentyl, -hexy1, -heptyl, -octyl, -nonyl, and the like.Accordingly, the various (open chain) secondary alkyl, as well as thecyclopentyl and cyclohexyl groupings as referred to in my copendingapplication Serial No. 538,201, which has become abandoned, may beunsubstituted as in the specific groupings already mentioned or monoorpoly-substituted by other alkyl groups such as in the di-isobutylemethyl (or 2,6-dimethylheptyl) group and the like.

The esters of the i vent on are p pared by suitable reaction betweenbenzoic acid anhydride or a benzoyl halide such as benzoyl chloride orbromide with the desired (open-chain) secondaryalky1(secondary)amino-propane] or -butanol. In preparing the esters starting with analkylaminoalkanol containing a non-tertiary alcohol group, the benzoylhalide or benzoic acid anhydride is reacted with an addition salt of thedesired (openchain)secondary alkylaminoalkanol containing the desired(open-chain) secondary-alkyl substituent on its amino group. Anadvantageous procedure for condensing the benzoyl compound with the saltof the aminoalkanol is to dissolve the aminoalkanol in an inert solventsuch as a chlorinated lower paraffin hydrocarbon as chloroform ormethylene chloride and the like and to convert it to its addition saltsuch as the hydrochloride by saturating the solution with dryhydrochloric acid gas, with cooling, and then to add to the solution anequal molal quantity of the benzoyl halide as benzoyl chloride dissolvedin an equal quantity of the same solvent, and heating the reactionmixture under reflex at 50 to 60 C., or higher, but preferably at thelower temperature range, then cooling the reaction mixture and removingthe solvent under vacuum, and if the free base is desired, then treatingthe reaction product suspended in water with sufficient suitable alkalias sodium carbonate monohydrate to liberate the free amino ester.

The invention may be illustrated by, but not restricted to, thefollowing examples:

Example 1--2-isopr0pylamino-1-butyl benzoate hydrochZoride.-A solutionof 13.1 grams (0.1 mol) of z-isopropylamino-l-butanol in 30 grams ofchloroform was satured with dry hydrogen chloride gas, with cooling. Asolution of 14.0 grams (0.1 mol) of benzoyl chloride in 30 grams ofchloroform was added and the solution was heated in a bath at 50-55 C.for four days under a reflux condenser protected from atmosphericmoisture. Then the solvent was removed by vacuum distillation while themixture was warmed on a water bath. Benzene was then added to the syrupyresidue and the reaction product crystallized out after the benzene wasremoved by vacuum distillation. The crystallized solid residue waswashed with anhydrous ether to remove any unreacted benzoyl chloride.The 2-isopropylamino-l-butyl benzoate hydrochloride obtained waspurified by two recrystallizations from absolute alcohol. It melted at144-145 C.

Example 2-2-diisobutyZmethyZamino-1-propyl benzoatehydrochloride-Melting at 108-1095 C.

was obtained by replacing the alkylaminoalkanol of Example 1 by themolal equivalent of Z-diisobutylmethylamino-l-propanol.

Example 3-2 diz'sobutylmethylamino-Z-butyl benzoatehydrochloride.lvlelting at 125-126 C. was obtained by replacing thealkylaminoalkanol of Example 1 by the molal equivalent of2-diisobutylmethylamino-l-butanol.

Included also as having similar local anesthetic use are other(open-chain) secondary-alkyl(secondary) amino-alkyl benzoates obtainedfrom alkylaminoalkanols having a non-tertiary alcohol group. Thesebenzoates embrace those having no substituent on the(open-chain)secondary alkyl nucleus as well as those having a loweralkyl radical linked to one or more of the openchain carbons. Preferablyin those having such hydrocarbon substituent on the (open-chain)-secondary-allryl group, the total number of. carbon atoms in the thussubstituted (open-chain)- secondary-alkyl group is less than eleven.These benzoates are prepared by the same procedure as disclosed inExample 1 by replacing the 2-150- propylamino-l-butanol of Example 1 bythe corresponding (open-chain) secondary alkylaminoalkanol, for example,2-(3-pentylamino)-l-, or Z-(l-heptylamino) -1-, or 2-(5-nonylamino) -1-butanol, or -propanol, 2-(sec.-butyl)amino-, or 2- (Z-hepytlamino) or2-isopropylamino-2methy1- 1-pr0panol,3- (B-pentylamino) or 3- (Z-heptylamino) or 3-(4-heptylamino)-, or 3-(2-octylamino) or3-[4-(2,6-dimethylheptyl)amino]-1- propanol, and 1-[4-(2,6-dimethylheptyl) aminol 2-propanol to give additional(open-chain)secondary-alkyl(secondary) amino-alkyl benzoatesrespectively as follows:

(a) 2-(3-pcntylamino)-1-butyl benzoa-te hydrochloride,

(b) 2-(l-heptylamino)l-butyl benzoate hydrochloride,

() Z-(S-nonylamino)1-butyl benzoate hydrochloride,

(d) 2-(3-pentylamino) -1-propyl benzoate hydrochloride,

(e) 2-(4-heptylamino) -1-propyl benzoate hydrochloride,

(f) 2-(5-nonylarnino)-1-propyl benzoate hydro-- chloride,

(5/) 2-sec.-butylamino--2-methyl-l-propyl benzoate hydrochloride,

(h) Z-(Z-heptylamino)-2-methyl-1-propyl benzoate hydrochloride,

(2) 2-isopropylamino-2-methyl-1-propy1 benzoate hydrochloride,

(9') 3-(3-pentylamino)-l-propyl benzoate hydrochloride,

(k) 3-(2-heptylamino) -1-propyl benzoate hydrochloride,

(l) 3-(4-heptylamino) -l-propyl benzoate hydrochloride,

(m) 3-(2-octylamino) -1-propyl benzoate hydrochloride,

(n) 3- l- (2,6-dimethylheptyl) -amino] -1-propyl benzoate hydrochloride,and

(0) l- [4- (2,6-dimethylheptyl) -amino\l 2l-propyl benzoatehydrochloride.

Also included are other such benzoates having an(open-chain)secondary-alkyl group attached to the amino nitrogen, whichare obtained from other (open-chain) secondary-alkyl(secondary)aminoalkanols having a tertiary alcohol group according to the procedureof Example 9 of my co-pending application Serial No. 538,201, byreacting the (open-chain)secondary-alkyl(secondary)amino-alkonal havingthe tertiary alcohol 4 group and containing the desired (open-chain)-secondary-alkyl substituent on its amino group with a substantialexcess, such as a 50% excess, of a benzoyl halide or benzoic acidanhydride to form the correponding benzamide, that is the N-benzoylderivative of the selected (openchain) secondary-alkyl (secondary)aminoalkanol, which amide is then rearranged to the corresponding esterhydrochloride, for example, by boiling in absolute alcohol with anexcess of concentrated hydrochloric acid. The resulting benzoates, forexample, obtained by starting with 1-isopropylamino-, or1-(3-penty1amino)-, or 1- (Z-heptylamino) or 1- (2-0ctylamino)-2-methyl- 2-propanol, or 1-isopropylamino-2-methyl (or ethyl)-2-butanol are illustrated by, but not restricted to, the following:

(p) 1-isopropylamino-2-methyl-2-propyl benzoate hydrochloride (q) 1-(3-pentylamino) -2methyl-2-propyl benzoate hydrochloride (r) 1-(Z-heptylamino) -2methyl-2-propyl benzoate hydrochloride, and

(s) l-(2-0ctylamino) -2-methyl-2-propyl benzoate hydrochloride.

Particularly advantageous among the compounds described herein are thoseof the general formula CSH5C00(CH2)7LCHRNHR1, in which n is selectedfrom 1 and 2, and R is selected from hydrogen and the methyl and ethylradicals, and R1 is the (open-chain)seco-ndary-alkyl radical with lessthan 11 carbon atoms. Especially efiective among this particular groupof compounds are those in which n is 1.

The esters of the invention are thus prepared from a wide variety of(open-chain) secondaryalkyl(secondary) amino alkanols selected from the-pr0panols and the -butanols, which alkanols then include a wide varietysuch as the 2-(openchain) secondary-alkyl(secondary) amino 1 alkanols,and 3-(open-chain)secondary-alkyl(sec ondary) amino 1 alkanols, and also1 (openchain) secondary alkyl(secondary) -amino-2-alkanols, in all ofwhich the alkanol group is selected' from the propanol and butanolgroups, which alkanol groups may contain the (openchain) secondary-alkyl(secondarylamino grouping as the sole substituent or may containadditional substituents' on the alkanol carbons, such as an alkylradical, preferably a lower alkyl radical.

The various suitable (open-chain)secondaryalkyl (secondary)amino-propanols and -butanols advantageously may be prepared bycondensing a ketone with a primary amino alcohol, with simultaneous orsubsequent reduction, the mechanism of which is the formation of anintermediate alkylidene amino alcohol, or the formation of anintermediate oxazolidine or the formation of an intermediate mixture ofboth. Such advantageous procedure is described in my or;- pendingapplication Serial No. 489,499, filed June 3, 1943, but now abandoned,reference to which is made for details of such procedure.

While the various examples show the preparation of the benzoatehydrochloride, if the free base is desired instead, it is prepared bydissolving or suspending the hydrochloride in a small volume of alcohol,diluting with water and treating with'an excess over the. stoichiometricquantity of sodium carbonate. The liberated free base is extracted withbenzene and recovered therefrom in known manner. If a salt of an acidother than hydrochloric acid is desiredthen to a solution of the freebase, for example, in benzene, there is added the stoichiometricquantity of the particular acid of which the addition salt is desired,and the solvent is then removed by evaporation, under vacuum if desired,and the desired addition salt obtained by crystallization.

The anesthetic compounds of the invention are the free amines, that is,the free bases. Ordinarily they are used in the form of addition salts,for example, as a hydrochloride, sulfate, sulfamate, tartrate, glycolateor other addition salt, as the free amines or bases are quite insolublein water. The selected salt should have sufficient solubility in waterto be completely soluble in the concentrations used, usually of theorder of 1% or less. The hydrochlorides and the glycolates are amongthose particularly therapeutically efiective. The esters in which the(openchain) secondary-alkyl substituent on the amino group has less thaneleven carbon atoms, are particularly effective.

While these various individual illustrations of the benzoic acid estersof the invention have been separately named as a certain butyl benzoateor as a certain propyl benzoate, as exemplified in starting with2-isopropylamino-1-butyl benzoate as in Example 1 and continuing fromthere through the disclosure ending withl-isopropylamino-2-ethyl-2-butyl benzoate hydrochloride, insofar asnomenclature is concerned each of the various individual esters embracedin the invention is either a benzoic acid ester of an (openchain)secondary aJkyHsecondary) amino pro- REFERENCES CITED The followingreferences are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 837,899 Emilewlcz Dec. 4, 19061,513,730 Adams et al. Nov. 4, 1924 2,363,081 Ringk Nov. 21, 19442,363,083 Ringk Nov. 21, 1944 2,442,797 Cope June 8, 1948 OTHERREFERENCES Goldberg et al., Journ. Am. Chem. Soc., vol. 61, pp.3562-3564 (1939).

Ringk et al., Journ. Am. Chem. $00., v01. 65, pp. 1222-1226 (1943).

